The Childhood Asthma Management Program (CAMP) has been in continuous existence for almost two decades, which makes it the largest randomized, placebo-controlled clinical trial with extended follow-up for children with mild to moderate asthma. As such, its cumulative data from baseline, active treatment, and post-treatment have proved to be an invaluable resource for not only assessing the efficacy and safety of long-term inhaled corticosteroid therapy in childhood, but for discovery of many other aspects of childhood asthma, including genetics and biomarkers.
Asthma; childhood; spirometry; airway hyperresponsiveness; inhaled corticosteroids; bronchodilators; bronchodilator response; allergy; pharmacogenomics; bone mineral density; vitamin D; linear growth; cataracts; hypothalamic–pituitary–adrenal axis; remission; progression; exacerbation; oral corticosteroids; nedocromil; forced expiratory volume in one second (FEV1); forced vital capacity (FVC); symptoms; health care utilization; phenotype; genetic polymorphism; eosinophils
Formal economic evaluation using a model-based approach is playing an increasingly important role in healthcare decision making.
To develop a model using an objective measure of lung function, prebronchodilator forced expiratory volume in 1 second as a percent of predicted (FEV1% predicted), as the primary independent factor to predict the frequency of adverse events related to exacerbation of asthma on a population level.
We developed a Markov simulation model of childhood asthma using data from the Childhood Asthma Management Program (CAMP). The primary outcomes were the result of asthma exacerbations defined as: hospitalizations, emergency department (ED) visits, and the need for oral corticosteroid therapy. Predicted monthly frequencies for each acute event were based on negative binomial regression equations estimated from the placebo arm of CAMP with covariates of age, prebronchodilator FEV1% predicted, time in study, prior hospitalizations, and prior nocturnal awakenings.
Simulated versus observed mean number of acute events were similar within the placebo and treatment groups. While the trial demonstrated treatment effects of 48% reduction in hospitalizations, 46% reduction in ED visits, and 44% reduction in the need for oral corticosteroid therapy at 48 months; the model simulated similar reductions of 49% in hospitalizations, 41% in ED visits, and 46% in the need for oral corticosteroid therapy.
Our findings suggest that longitudinal intervention effects may be modeled through FEV1% predicted to estimate hospitalizations, ED visits, and need for oral corticosteroid therapy in childhood asthma for planning and evaluation purposes.
asthma; pediatric patients; lung function; FEV percent predicted; hospitalizations; emergency department visits; model
Rationale: Low vitamin D levels are associated with asthma and decreased airway responsiveness. Treatment with inhaled corticosteroids improves airway responsiveness and asthma control.
Objectives: To assess the effect of vitamin D levels on prebronchodilator FEV1, bronchodilator response, and responsiveness to methacholine (PC20, provocative concentration of methacholine producing a 20% decline in FEV1) in patients with asthma treated with inhaled corticosteroids.
Methods: We measured 25-hydroxyvitamin D levels in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program. We divided subjects into the vitamin D sufficiency (>30 ng/ml), insufficiency (20–30 ng/ml), and deficiency (<20 ng/ml) groups. Covariates included age, treatment, sex, body mass index, race, history of emergency department visits, hospitalizations, and season that vitamin D specimen was drawn. Our main outcome measures were change in prebronchodilator FEV1, bronchodilator response, and PC20 from enrollment to 8–12 months.
Measurements and Main Results: Of the 1,024 subjects, 663 (65%) were vitamin D sufficient, 260 (25%) were insufficient, and 101 (10%) were deficient. Vitamin D–deficient subjects were more likely to be older, African American, and have a higher body mass index compared with the vitamin D–sufficient and insufficient subjects. In the inhaled corticosteroid treatment group, prebronchodilator FEV1 increased from randomization to 12 months by 140 ml in the vitamin D–deficient group and prebronchodilator FEV1 increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group (P = 0.0072), in adjusted models.
Conclusions: In children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency.
asthma; vitamin D; lung function; forced expiratory volume; children
The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height.
We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry.
Mean adult height was 1.2 cm lower (95% confidence interval [CI], −1.9 to −0.5) in the budesonide group than in the placebo group (P = 0.001) and was 0.2 cm lower (95% CI, −0.9 to 0.5) in the nedocromil group than in the placebo group (P = 0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (−0.1 cm for each microgram per kilogram of body weight) (P = 0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (−1.3 cm; 95% CI, −1.7 to −0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants.
The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative.
The Commonwealth of Massachusetts increased the copayment for prescription drugs by $1.50 for Medicaid (MassHealth) beneficiaries in 2003. We sought to determine the likely health outcomes and cost shifts attributable to this copayment increase using the example of inhaled corticosteroids (ICS) use among adult asthmatic Medicaid beneficiaries.
We compared the predicted costs and health outcomes projected over a 1-year time horizon with and without the increase in copayment from the perspective of MassHealth, providers, pharmacies, and MassHealth beneficiaries by employing decision analysis simulation model.
In a target population of 17,500 adult asthmatics, increased copayments from 50¢ to $2.00 would result in an additional 646 acute events per year, caused by increased drug nonadherence. Annual combined net savings for the state and federal governments would be $2.10 million. Projected MassHealth savings are attributable to both decreased drug utilization and lower pharmacy reimbursement rates; these more than offset the additional costs of more frequent acute exacerbations. Pharmacies would lose $1.98 million in net revenues, MassHealth beneficiaries would pay an additional $0.28 million, and providers would receive additional $0.16 million.
Over its first year of implementation, increase in the prescription drug copayment is expected to produce more frequent acute exacerbations among asthmatic MassHealth beneficiaries who use ICS and to shift the financial burden from government to other stakeholders.
asthma; copayment; medicaid; prescription drug
Omalizumab (trade name Xolair) is approved by the US Food and Drug Administration for treatment of moderate-to-severe allergic asthma. Given the high acquisition cost of omalizumab, its role and cost-effectiveness in disease management require definition.
We sought to identify the clinical and economic circumstances under which omalizumab might or might not be a cost-effective option by using a mathematic model.
We merged published data on clinical and economic outcomes (including acute event incidence, frequency/severity of hospitalizations, and health-related quality of life) to project 10-year costs, quality-adjusted life years (QALYs), and cost-effectiveness of treatment with omalizumab in addition to inhaled corticosteroids. Sensitivity analyses were conducted by using input data ranges from a variety of sources (published clinical trials and observational databases).
For patients with baseline acute event rates, omalizumab conferred an additional 1.7 quality-adjusted months at an incremental cost of $131,000 over a 10-year planning horizon, implying a cost-effectiveness ratio of $821,000 per QALY gained. For patients with 5 times the baseline acute event rate, the cost-effectiveness ratio was $491,000 per QALY gained. The projected cost-effectiveness ratio could fall within a range of other programs that are widely considered to be cost-effective if the cost of omalizumab decreases to less than $200.
Omalizumab is not cost-effective for most patients with severe asthma. The projected cost-effectiveness ratios could fall within a favorable range if the cost of omalizumab decreases significantly.
Based on the high cost of omalizumab, it is especially important that clinicians explore alternative medications for asthma before initiating omalizumab.
Omalizumab; cost-effectiveness; asthma; anti-IgE
Acute exacerbations are a significant source of morbidity and mortality associated with chronic obstructive pulmonary disease. Among patients with COPD, some patients suffer an inordinate number of exacerbations while others remain relatively protected. We undertook a study to determine the clinical factors associated with "frequent exacerbator" status within a population of subjects with severe COPD.
Case-control cohort recruited from two Boston-area practices. All subjects had GOLD stage 3 or 4 (FEV1 ≤50% predicted) COPD. "Frequent exacerbators" (n=192) had an average of ≥2 moderate-to-severe exacerbations per year while "non-exacerbators" (n=153) had no exacerbations in the preceding 12 months. Multivariate logistic regression was performed to determine the significant clinical predictors of "frequent exacerbator" status.
Physician-diagnosed asthma was a significant predictor of frequent exacerbations. Within a subset of our cohort, the modified Medical Research Council dyspnea score and FEF25–75 % predicted were also significant clinical predictors of frequent exacerbator status (p<0.05). Differences in exacerbation frequency were not found to be due to increased current tobacco use or decreased rates of maintenance medication use.
Within our severe COPD cohort, a history of physician-diagnosed asthma was found to be a significant clinical predictor of frequent exacerbations. Although traditional risk factors such as decreased FEV1% predicted were not significantly associated with frequent exacerbator status, lower mid-expiratory flow rates, as assessed by FEF 25–75 % predicted, were significantly associated with frequent exacerbations in a subset of our cohort.
Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in asthmatic children.
To explore whether IUS exposure is associated with increased airway responsiveness among children with asthma, and whether IUS modifies the response to treatment with inhaled corticosteroids (ICS).
To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma we performed a repeated-measures analysis of methacholine PC20 data from the Childhood Asthma Management Program (CAMP), a four-year, multicenter, randomized double masked placebo controlled trial of 1041 children ages 5–12 comparing the long term efficacy of ICS with mast cell stabilizing agents or placebo.
Although improvement was seen in both groups, asthmatic children with IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared to unexposed children (p=.01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC20 compared to untreated children (1.25 fold-increase, 95% CI 1.03, 1.50, p=.02) the beneficial effects of budesonide were attenuated among children with a history of IUS exposure (1.04 fold-increase, 95% CI 0.65, 1.68, p=.88).
IUS reduces age-related improvements in airway responsiveness among asthmatic children. Moreover, IUS appears to blunt the beneficial effects of ICS use on airways responsiveness. These results emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.
asthma; in utero smoke exposure; airway responsiveness; inhaled corticosteroids
Asthma exacerbations, most often due to respiratory tract infections, are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs. Vitamin D status may play a role in preventing asthma exacerbations.
To assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations.
We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected from 1,024 mild to moderate persistent asthmatic children at the time of enrollment in a multi-center clinical trial of children randomized to receiving budesonide, nedocromil, or placebo (as-needed beta-agonists), the Childhood Asthma Management Program. Using multivariable modeling we examined the relationship between baseline vitamin D level and the odds of any hospitalization or emergency department (ED) visit over the 4 years of the trial.
35% of all subjects were vitamin D insufficient, as defined by a level ≤ 30 ng/ml 25(OH)D. Mean vitamin D levels were lowest in African-American subjects, and highest in whites. After adjusting for age, sex, BMI, income, and treatment group, insufficient vitamin D status was associated with a higher odds of any hospitalization or ED visit (odds ratio [OR] 1.5 [95% confidence interval [CI]: 1.1 – 1.9] P =0.01).
Vitamin D insufficiency is common in this population of North American children with mild to moderate persistent asthma, and is associated with higher odds of severe exacerbation over a four year period.
Asthma; Vitamin D; inhaled corticosteroids; asthma exacerbations
Daily controller medication use is recommended for children with persistent asthma to achieve asthma control.
To examine patterns of inhaled corticosteroid (ICS) use and asthma control in an observational study of children and adolescents with mild-to-moderate asthma (the Childhood Asthma Management Program Continuation Study).
We assessed patterns of ICS use during a 12-month period (consistent, intermittent, and none) and asthma control (well controlled vs poorly controlled). Multivariate logistic regression examined the association between pattern of ICS use and asthma control.
Of 914 patients enrolled, 425 were recommended to continue receiving ICS therapy in the Childhood Asthma Management Program Continuation Study. Of these patients, 46% reported consistent ICS use and 20% reported no ICS use during year 1. By year 4, consistent ICS use decreased to 20%, whereas no ICS use increased to 57%; poorly controlled asthma was reported in 18% of encounters. In multivariate models controlling for age, sex, forced expiratory volume in 1 second, and asthma severity assessment, patients reporting consistent ICS use during a 12-month period were more likely to report poor asthma control (odds ratio, 1.6; 95% confidence interval, 1.2–2.1) compared with those reporting no ICS use.
In this observational study of children and adolescents with mild-to-moderate asthma, most did not report continued use of ICS. Patients recommended to continue receiving ICS therapy and reporting consistent ICS use were less likely to report well-controlled asthma even after controlling for markers of asthma severity. Although residual confounding by severity cannot be ruled out, many children and adolescents may not achieve well-controlled asthma despite consistent use of ICS.
Weak and inconsistent correlations between measurements of asthma health status suggest that the disease is composed of non-overlapping components.
Factor analysis was used to explore the relationships between measures of asthma morbidity and to identify heterogeneous components of asthma health status in 5 to 12 year old children. Results were compared across time (baseline and 48 month visit) and treatment arms.
Analyses were conducted in 7 different study windows in a database from a large clinical trial of children with mild to moderate asthma (n=1041). Measurements of lung function, symptoms and health care utilizations from daily diary cards, serum IgE levels, total eosinophil count, skin test positivity, and airway hyper-responsiveness were included. Data on fractional exhaled nitric oxide (FENO) and sputum eosinophil cationic protein (ECP) was included in a subgroup of patients.
In each of the study windows, factor analysis identified 5 factors which explained between 50% and 60% of the common variance. Factors identified included: (1) inflammatory markers, (2) symptoms/medication use, (3) asthma exacerbations, and measures of lung function which subdivided into (4) Forced Expiratory Volume (FEV1 ) and Forced Vital Capacity (FVC), (5) Bronchodilator response and the FEV1/FVC ratio. Exploratory analyses suggest that FENO comprise the atopy/inflammatory marker factor, and sputum measurements comprise a 6th, separate factor.
The consistent identification of a five factor structure across time and treatment arms suggests that each of these factors provides independent information in the assessment of asthma.
This study confirms the importance of a multidimensional approach to asthma in the clinical setting.
factor analysis; asthma health status; components; associations; morbidity
Among asthmatics, bronchodilator response (BDR) to inhaled ß2- adrenergic agonists is variable, and the significance of a consistent response over time is unknown.
We assessed baseline clinical variables and determined the clinical outcomes associated with a consistently positive BDR over 4 years in children with mild-moderate persistent asthma.
In the 1,041 participants in the Childhood Asthma Management Program (CAMP), subjects with a change in FEV1 of 12% or greater (and 200mLs) after inhaled ß2 agonist at each of their yearly follow-up visits (consistent BDR) were compared with those who did not have a consistent BDR.
We identified 52 children with consistent BDR over the 4-year trial. Multivariable logistic regression modeling demonstrated that baseline pre-bronchodilator FEV1 (OR=0.71, p<0.0001), log 10 IgE level (OR=1.97, p=0.002), and lack of treatment with inhaled corticosteroids (OR=0.31, p=0.009) were associated with a consistent BDR. Individuals who had a consistent BDR had more hospital visits (p=0.007), required more prednisone bursts (p=0.0007), had increased nocturnal awakenings due to asthma (p<0.0001), and missed more days of school (p=0.03) than non-responders during the 4-year follow-up.
We have identified predictors of consistent BDR and determined that this phenotype is associated with poor clinical outcomes.
asthma; consistent bronchodilator response; outcomes
To evaluate phenotypic and genetic variables associated with a poor long-term response to inhaled corticosteroid therapy for asthma, based independently on lung function changes or asthma exacerbations.
Materials & methods
We tested 17 phenotypic variables and polymorphisms in FCER2 and CRHR1 in 311 children (aged 5–12 years) randomized to a 4-year course of inhaled corticosteroid during the Childhood Asthma Management Program (CAMP).
Predictors of recurrent asthma exacerbations are distinct from predictors of poor lung function response. A history of prior asthma exacerbations, younger age and a higher IgE level (p < 0.05) are associated with recurrent exacerbations. By contrast, lower bronchodilator response to albuterol and the minor alleles of RS242941 in CRHR1 and T2206C in FCER2 (p < 0.05) are associated with poor lung function response. Poor lung function response does not increase the risk of exacerbations and vice versa (p = 0.72).
Genetic and phenotypic predictors of a poor long-term response to inhaled corticosteroids differ markedly depending on definition of outcome (based on exacerbations vs lung function). These findings are important in comparing outcomes of clinical trials and in designing future pharmacogenetic studies.
asthma; corticosteroid; exacerbation; lung function; pharmacogenetics
Rationale: Airway responsiveness is a prognostic marker for asthma symptoms in later life.
Objectives: To evaluate characteristics responsible for persistence of airway responsiveness in children with asthma.
Methods: A total of 1,041 children, initially aged 5–12 years, with mild to moderate persistent asthma enrolled in the Childhood Asthma Management Program (CAMP) were studied prospectively for 8.6 ± 1.8 years with methacholine challenges yearly.
Measurements and Main Results: Least squares geometric mean models were fit to determine effects of sex and age on airway responsiveness (provocative concentration producing 20% decrease in FEV1 [PC20]). Multiple linear regression analysis was performed to determine factors at baseline and over time, which were associated with PC20 at end of follow-up. A total of 7,748 methacholine challenges were analyzed. PC20 increased with age, with boys having greater increase after age 11 years than girls (P < 0.001). The divergence coincided with the mean age for Tanner stage 2. Postpubertal girls had greater airway responsiveness, even after adjustment for FEV1 and other potential confounders. Although multivariable regression analyses noted a variety of factors that influenced airway responsivness in both sexes, a history of hay fever (β= −0.30, P = 0.005), respiratory allergy (β= −0.32, P = 0.006), or recent inhaled corticosteroid usage (β= −0.18, P = 0.02) were associated with decrements in final log PC20 only in girls.
Conclusions: Airway responsiveness (PC20) is more severe in the postpubertal female with asthma than in males. Although there are factors associated with airway responsiveness in both males and females, sex-specific factors may contribute to new insights into asthma pathogenesis.
methacholine; PC20; FEV1; bronchoconstriction
To assess the practice-level effects of (1) a physician peer leader intervention and (2) peer leaders in combination with the introduction of asthma education nurses to facilitate care improvement. And, to compare findings with previously reported patient-level outcomes of trial enrollees.
Data were included on children 5–17 years old with asthma in 40 primary care practices, affiliated with managed health care plans enrolled in the Pediatric Asthma Care Patient Outcomes Research Team (PORT) randomized trial.
Primary care practices were randomly assigned to one of two care improvement arms or to usual care. Automated claims data were analyzed for 12-month periods using a repeated cross-sectional design. The primary outcome was evidence of at least one controller medication dispensed among patients with persistent asthma. Secondary outcomes included controller dispensing among all identified asthmatics, evidence of chronic controller use, and the dispensing of oral steroids. Health service utilization outcomes included numbers of ambulatory visits and hospital-based events.
The proportion of children with persistent asthma prescribed controllers increased in all study arms. No effect of the interventions on the proportion receiving controllers was detected (peer leader intervention effect 0.01, 95 percent confidence interval [CI]: −0.07, 0.08; planned care intervention effect −0.03, 95 percent CI: −0.09, 0.02). A statistical trend was seen toward an increased number of oral corticosteroid bursts dispensed in intervention practices. Significant adjusted increases in ambulatory visits of 0.08–0.10 visits per child per year were seen in the first intervention year, but only a statistical trend in these outcomes persisted into the second year of follow-up. No differences in hospital-based events were detected.
This analysis showed a slight increase in ambulatory asthma visits as a result of asthma care improvement interventions, using automated data. The absence of detectable impact on medication use at the practice level differs from the positive intervention effect observed in patient self-reported data from trial enrollees. Analysis of automated data on nonenrollees adds information about practice-level impact of care improvement strategies. Benefits of practice-level interventions may accrue disproportionately to the subgroup of trial enrollees. The effect of such interventions may be less apparent at the level of practices or health plans.
Asthma care; randomized controlled trial; chronic care model; physician behavior change
A great deal of successful work has been done in the area of EMR development, implementation, and evaluation. Less work has been done in the area of automated systems for patients. Efforts to link data at multiple levels – the patient, the case manager, and the clinician have been rudimentary to-date.
In this paper we present a model information system that integrates patient health information across multiple domains to support the monitoring and care of children with persistent asthma. The system has been developed for use in a multi-specialty group practice and includes three primary components: 1) a patient-centered telephone-linked communication system; 2) a web-based alert reporting and nurse case-management system; and 3) EMR-based provider communication to support clinical decision making at the point-of-care.
The system offers a model for a new level of connectivity for health information that supports customized monitoring, IT-enabled nurse case-managers, and the delivery of longitudinal data to clinicians to support the care of children with persistent asthma.
Systems like the one described are well -suited, perhaps essential, technologies for the care of children and adults with chronic conditions such as asthma.